Combination therapy with anti-pvrig antibodies formulations, anti-tigit antibodies, and anti-pd-1 antibodies

Abstract

The present invention is directed to combination treatments with anti-PVRIG antibodies, anti-TIGIT antibodies, and anti-PD-1 antibodies, in particular nivolumab, using stable liquid pharmaceutical formulations thereof.

1 . A method of treatment for cancer by blocking DNAM axis in a patient in need thereof, the method comprising administering BMS-986207, Nivolumab, and an anti-poliovirus receptor related immunoglobulin domain containing (anti-PVRIG) antibody, wherein said anti-PVRIG antibody is administered as a stable liquid pharmaceutical formulation and, wherein the stable liquid pharmaceutical formulation of the anti-PVRIG antibody comprises:
 (a) an anti-PVRIG antibody, wherein said anti-PVRIG antibody comprises:
 i) a heavy chain variable domain comprising the vhCDR1, vhCDR2, and vhCDR3 from the heavy chain variable domain of CHA.7.518.1.H4(S241P) (SEQ ID NO:4), and 
 ii) a light chain variable domain comprising the vlCDR1, vlCDR2, and vlCDR3 from the light chain variable domain of CHA.7.518.1.H4(S241P) (SEQ ID NO:9); 
   (b) from 10 mM to 100 mM histidine;   (c) from 30 mM to 100 mM NaCl;   (d) from 20 mM to 150 mM L-Arginine; and   (e) from 0.005% to 0.1% w/v polysorbate 80,   wherein the composition has a pH from 5.5 to 7.0.   
     
     
         2 . The method of treatment according to  claim 1 , wherein the patient is refractory to one or more prior cancer therapies, and/or wherein the patient has relapsed after one or more prior cancer therapies. 
     
     
         3 . (canceled) 
     
     
         4 . The method of treatment according to  claim 1 , wherein the patient has received from about 1 to about 20 prior cancer therapies. 
     
     
         5 . The method of treatment according to  claim 1 , wherein the patient has exhausted, or is refractory to, available standard therapies, or wherein the patient is not a candidate for available standard therapies. 
     
     
         6 . (canceled) 
     
     
         7 . The method of treatment according to  claim 1 , wherein the patient is refractory to treatment with immune checkpoint inhibitor. 
     
     
         8 . The method of treatment according to  claim 7 , wherein the immune checkpoint inhibitor is selected from the group consisting of: an anti-PVRIG antibody, an anti-TIGIT antibody, anti- PD-1 antibody, an anti-CTLA-4 antibody, an anti-PD-L1 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, and an anti-BTLA antibody, an anti-DNAM1 antibody, an anti-ICOS antibody, an anti-4-1bb antibody, an anti-GITR antibody, an anti-OX40 antibody, an anti-CD96 antibody, an anti-B7-H4 antibody, an anti-B7-H3 antibody, an anti-VISTA antibody, an anti-CD27 antibody, an anti-CD40 antibody, an anti-PVR antibody, an anti-PVRL2 antibody and an anti-CD137 antibody. 
     
     
         9 . The method of treatment according to  claim 2 , wherein the patient is refractory to treatment with an anti-PD-L1 antibody; and/or wherein the patient is refractory to treatment with an anti-PD-1 antibody. 
     
     
         10 . (canceled) 
     
     
         11 . The method of treatment according to  claim 1 , wherein the cancer is chemotherapy resistant cancer. 
     
     
         12 . The method of treatment according to  claim 11 , wherein the cancer is platinum resistant cancer. 
     
     
         13 . The method of treatment according to  claim 1 , wherein the cancer is advanced cancer. 
     
     
         14 . The method of treatment according to  claim 1 , wherein the cancer is metastatic cancer. 
     
     
         15 . The method of treatment according to  claim 1 , wherein said BMS-986207, nivolumab, and an anti-PVRIG antibody are administered sequentially or simultaneously, in any order, and in one or more formulations. 
     
     
         16 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody is diluted prior to administration to a subject; and/or wherein said anti-PVRIG antibody is diluted in saline prior to administration to a subject. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody comprises the CH1-hinge-CH2-CH3 region from IgG1, IgG2, IgG3, or IgG4, wherein said hinge region optionally comprises mutations: or wherein said anti-PVRIG antibody comprises a CH1-hinge-CH2-CH3 sequence of IgG4 (SEQ ID NO:17 or SEQ ID NO:56). 
     
     
         20 . The method of treatment according to  claim 1 , wherein said heavy chain variable domain is from the heavy chain variable domain of CHA.7.518.1.H4(S241P) (SEQ ID NO:4) and said light chain variable domain is from the light chain variable domain of CHA.7.518.1.H4(S241P) (SEQ ID NO:9). 
     
     
         21 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody comprises a CL region of human kappa 2 light chain. 
     
     
         22 . The method of treatment according to  claim 1 , wherein said pharmaceutical formulation comprises from 10 mM to 80 mM histidine, from 15 mM to 70 mM histidine, from 20 mM to 60 mM histidine, from 20 mM to 50 mM histidine, from 20 mM to 30 mM histidine, or about 25 mM histidine. 
     
     
         23 . (canceled) 
     
     
         24 . The method of treatment according to  claim 1 , wherein said pharmaceutical formulation comprises from 30 mM to 100 mM NaCl, from 30 mM to 90 mM NaCl, from 40 mM to 80 mM NaCl, from 30 mM to 70 mM histidine, from 45 mM to 70 mM NaCl, or about 60 mM NaCl. 
     
     
         25 . (canceled) 
     
     
         26 . The method of treatment according to  claim 1 , wherein said pharmaceutical formulation comprises from 20 mM to 140 mM L-arginine, from 30 mM to 140 mM L-arginine, from 40 mM to 130 mM L-arginine, from 50 mM to 120 mM L-arginine, from 60 mM to 110 mM L-arginine, from 70 mM to 110 mM L-arginine, from 80 mM to 110 mM L-arginine, from 90 mM to 110 mM L-arginine, or about 100 mM L-arginine. 
     
     
         27 . (canceled) 
     
     
         28 . The method of treatment according to  claim 1 , wherein said pharmaceutical formulation comprises from 0.006% to 0.1% w/v polysorbate 80, from 0.007% to 0.09% w/v polysorbate 80, from 0.008% to 0.08% w/v polysorbate 80, from 0.009% to 0.09% w/v polysorbate 80, from 0.01% to 0.08% w/v polysorbate 80, from 0.01% to 0.07% w/v polysorbate 80, from 0.01% to 0.07% w/v polysorbate 80, or from 0.01% to 0.06% w/v polysorbate 80, or from 0.009% to 0.05% w/v polysorbate 80, or about 0.01% w/v polysorbate 80. 
     
     
         29 . (canceled) 
     
     
         30 . The method of treatment according to  claim 1 , wherein said pH is from 6 to 7.0, from 6.3 to 6.8, or 6.5+/−0.2. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody is at a concentration of from 10 mg/mL to 40 mg/mL, 15 mg/mL to 40 mg/mL, 15 mg/mL to 30 mg/mL, 10 mg/mL to 25 mg/mL, or 15 mg/mL to 25 mg/mL. 
     
     
         34 . The method of treatment according to  claim 1 , wherein said formulation is stable at 2° C. to 8° C. for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. 
     
     
         35 . The method of treatment according to  claim 1 , wherein said formulation is stable at about 20° C. to 25° C. for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. 
     
     
         36 . The method of treatment according to  claim 1 , wherein said formulation is stable at 35° C. to 40° C. for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks. 
     
     
         37 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody is at a concentration of about 20 mg/mL. 
     
     
         38 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody formulation comprises:
 a) a heavy chain comprising:
 i) a VH-CH1-hinge-CH2-CH3, wherein the VH is from CHA.7.518.1.H4(S241P) (SEQ ID NO:4) and wherein the CH1-hinge-CH2-CH3 region is from IgG4; and 
   b) a light chain comprising:
 i) a VL-CL, wherein the VL from CHA.7.518.1.H4(S241P) (SEQ ID NO:9) and wherein the CL region is from human kappa 2 light chain. 
   
     
     
         39 . The method of treatment according to  claim 38 , wherein said hinge region comprises mutations. 
     
     
         40 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody formulation comprises:
 i) a heavy chain comprising the heavy chain from CHA.7.518.1.H4(S241P) (SEQ ID NO:8); and   ii) a light chain comprising the light chain from CHA.7.518.1.H4(S241P) (SEQ ID NO:13).   
     
     
         41 . The method of treatment according to  claim 1 , said anti-PVRIG antibody formulation comprising:
 (a) an anti-PVRIG antibody, wherein said anti-PVRIG antibody comprises:
 i) a heavy chain variable domain comprising the vhCDR1, vhCDR2, and vhCDR3 from the heavy chain variable domain of CHA.7.518.1.H4(S241P) (SEQ ID NO:4), and 
 ii) a light chain variable domain comprising the vlCDR1, vlCDR2, and vlCDR3 from the light chain variable domain of CHA.7.518.1.H4(S241P) (SEQ ID NO:9); 
   (b) about 25 mM histidine;   (c) about 60 mM NaCl;   (d) about 100 mM L-Arginine; and   (e) about 0.01% % w/v polysorbate 80,   wherein the composition has a pH from 6.5+/−0.2.   
     
     
         42 . The method of treatment according to  claim 1 , said anti-PVRIG antibody formulation comprising:
 (a) an anti-PVRIG antibody, wherein said anti-PVRIG antibody comprises:
 i) a heavy chain comprising the heavy chain from CHA.7.518.1.H4(S241P) (SEQ ID NO:8); and 
 ii) a light chain comprising the light chain from CHA.7.518.1.H4(S241P) (SEQ ID NO:13); 
   (b) about 25 mM histidine;   (c) about 60 mM NaCl;   (d) about 100 mM L-Arginine; and   (e) about 0.01% % w/v polysorbate 80,   
       wherein the composition has a pH from 6.5+/−0.2. 
     
     
         43 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody is administered at a dosage of about 0.01 mg/kg to about 20 mg/kg of the anti-PVRIG antibody or about 0.01 mg/kg to about 10 mg/kg of the anti-PVRIG antibody or about 10 mg/kg to about 20 mg/kg of the anti-PVRIG antibody; or about 0.01 mg/kg, 0.03 mg/kg. 0.1 mg/kg. 0.3 mg/kg. 1 mg/kg. 3 mg/kg. 10 mg/kg, or 20 mg/kg of the anti-PVRIG antibody. 
     
     
         44 . (canceled) 
     
     
         45 . The method of treatment according to  claim 1 , wherein said nivolumab is administered at a dosage of about 360 mg of nivolumab or 480 mg of nivolumab. 
     
     
         46 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody is administered 20 mg/kg every 4 weeks. 
     
     
         47 . The method of treatment according to  claim 1 , wherein said BMS-986207 antibody is administered every 4 weeks. 
     
     
         48 . The method of treatment according to  claim 1 , wherein said BMS-986207 antibody is administered at 480 mg of BMS-986207. 
     
     
         49 . The method of treatment according to  claim 1 , wherein said anti-PVRIG antibody is administered at a dosage of about 20 mg/kg, wherein BMS-986207 antibody is administered at a dosage of about 480 mg, and wherein nivolumab is administered at a dosage of about 480 mg; or
 said anti-PVRIG antibody is administered at a dosage of about 20 mg/kg, wherein BMS-986207 antibody is administered at a dosage of about 360 mg, and wherein nivolumab is administered at a dosage of about 360 mg.   
     
     
         50 . (canceled) 
     
     
         51 . The method of treatment according to  claim 49 , wherein said anti-PVRIG antibody, BMS-986207 antibody, and nivolumab are administered, optionally intravenously, every 4 weeks. 
     
     
         52 . (canceled) 
     
     
         53 . The method of treatment according to  claim 1 , wherein a subject for treatment comprises, or treatment efficacy is indicated based on, one of the following, as compared to a control or an untreated patient or said patient prior to treatment:
 a. an increase in serum IFNγ of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, or 1000%;   b. an increase in the CD8/CD4 ratio of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, or 1000%;   c. an increase in percent proliferating CD8+CD45RA-CCR7-effector memory (EM) T-cells by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, or 1000%;   d. an increase in percent proliferating (Ki67% positive) CD8+CD45RA-CCR7-effector memory (EM) T-cells by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, or 1000%; and/or   e. an increase activation of immune populations as exhibited by an increase in CD69+ expression on CD4 and/or CD8 T-cells and/or NK cells by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 725%, 750%, 775%, 800%, 825%, 850%, 875%, 900%, 925%, 950%, 975%, 1000%, 1025%, 1050%, 1075%, 1100%, 1125%, 1150%, 1175%, 1200%,1225%, 1250%, 1275%, 1300%,1325%, 1350%, 1375%, 1400%,1425%, 1450%, 1475%, 1500%,1525%, 1550%, 1575%, 1600%,1625%, 1650%, 1675%, 1700%,1725%, 1750%, 1775%, 1800%,1825%, 1850%, 1875%, 1900%,1925%, 1950%, 1975%, or 2000%.   
     
     
         54 . (canceled) 
     
     
         55 . The method of treatment according to  claim 1 , wherein a subject for treatment comprises, or treatment efficacy is indicated based on, one of the following, as compared to a control or an untreated patient or said patient prior to treatment:
 a. an increase in serum IFNγ of at least about 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.25-fold, 2.5-fold, 2.75-fold, 3-fold, 3.25-fold, 3.5-fold, 3.75-fold, 4-fold, 4.25-fold, 4.5-fold, 4.75-fold, 5-fold, 5.25-fold, 5.5-fold, 5.75-fold, 6-fold, 6.25-fold, 6.5-fold, 6.75-fold, 7-fold, 7.25-fold, 7.5-fold, 7.75-fold, 8-fold, 8.25-fold, 8.5-fold, 8.75-fold, 9-fold, 9.25-fold, 9.5-fold, 9.75-fold, 10-fold, 10.25-fold, 10.5-fold, 10.75-fold or 11-fold;   b. an increase in the CD8/CD4 ratio of at least about 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.25-fold, 2.5-fold, 2.75-fold, 3-fold, 3.25-fold, 3.5-fold, 3.75-fold, 4-fold, 4.25-fold, 4.5-fold, 4.75-fold, 5-fold, 5.25-fold, 5.5-fold, 5.75-fold, 6-fold, 6.25-fold, 6.5-fold, 6.75-fold, 7-fold, 7.25-fold, 7.5-fold, 7.75-fold, 8-fold, 8.25-fold, 8.5-fold, 8.75-fold, 9-fold, 9.25-fold, 9.5-fold, 9.75-fold, 10-fold, 10.25-fold, 10.5-fold, 10.75-fold or 11-fold;   c. an increase in percent proliferating CD8+CD45RA-CCR7-effector memory (EM) T-cells by at least about 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.25-fold, 2.5-fold, 2.75-fold, 3-fold, 3.25-fold, 3.5-fold, 3.75-fold, 4-fold, 4.25-fold, 4.5-fold, 4.75-fold, 5-fold, 5.25-fold, 5.5-fold, 5.75-fold, 6-fold, 6.25-fold, 6.5-fold, 6.75-fold, 7-fold, 7.25-fold, 7.5-fold, 7.75-fold, 8-fold, 8.25-fold, 8.5-fold, 8.75-fold, 9-fold, 9.25-fold, 9.5-fold, 9.75-fold, 10-fold, 10.25-fold, 10.5-fold, 10.75-fold or 11-fold;   d. an increase in percent proliferating (Ki67% positive) CD8+CD45RA-CCR7-effector memory (EM) T-cells by at least about 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.25-fold, 2.5-fold, 2.75-fold, 3-fold, 3.25-fold, 3.5-fold, 3.75-fold, 4-fold, 4.25-fold, 4.5-fold, 4.75-fold, 5-fold, 5.25-fold, 5.5-fold, 5.75-fold, 6-fold, 6.25-fold, 6.5-fold, 6.75-fold, 7-fold, 7.25-fold, 7.5-fold, 7.75-fold, 8-fold, 8.25-fold, 8.5-fold, 8.75-fold, 9-fold, 9.25-fold, 9.5-fold, 9.75-fold, 10-fold, 10.25-fold, 10.5-fold, 10.75-fold or 11-fold; and/or   e. an increase in activation of immune populations as exhibited by an increase in CD69+ expression on CD4 and/or CD8 T-cells and/or NK cells by at least about 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.25-fold, 2.5-fold, 2.75-fold, 3-fold, 3.25-fold, 3.5-fold, 3.75-fold, 4-fold, 4.25-fold, 4.5-fold, 4.75-fold, 5-fold, 5.25-fold, 5.5-fold, 5.75-fold, 6-fold, 6.25-fold, 6.5-fold, 6.75-fold, 7-fold, 7.25-fold, 7.5-fold, 7.75-fold, 8-fold, 8.25-fold, 8.5-fold, 8.75-fold, 9-fold, 9.25-fold, 9.5-fold, 9.75-fold, 10-fold, 10.25-fold, 10.5-fold, 10.75-fold 11-fold, 11.25-fold, 11.5-fold, 11.75-fold, 12-fold, 12.25-fold, 12.5-fold, 12.75-fold, 13-fold, 13.25-fold, 13.5-fold, 13.75-fold, 14-fold, 14.25-fold, 14.5-fold, 14.75-fold, 15-fold, 15.25-fold, 15.5-fold, 15.75-fold, 16-fold, 16.25-fold, 16.5-fold, 16.75-fold, 17-fold, 17.25-fold, 17.5-fold, 17.75-fold, 18-fold, 18.25-fold, 18.5-fold, 18.75-fold, 19-fold, 19.25-fold, 19.5-fold, 19.75-fold, 20-fold, 20.25-fold, 20.5-fold, 20.75-fold, 21-fold, 21.25-fold, 21.5-fold, 21.75-fold, or 22-fold.   
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . (canceled) 
     
     
         70 . (canceled) 
     
     
         71 . (canceled) 
     
     
         72 . (canceled) 
     
     
         73 . (canceled) 
     
     
         74 . The method of treatment according to  claim 55 , wherein one or more of the increases are determined or measured in circulating cells from peripheral blood. 
     
     
         75 . The method of treatment according to  claim 1 , wherein said cancer is selected from the group consisting of prostate cancer, liver cancer (HCC), colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC; including refractory MSS colorectal), CRC (MSS unknown), ovarian cancer (including ovarian carcinoma), endometrial cancer (including endometrial carcinoma), breast cancer, stomach cancer, cervical cancer, head and neck cancer, thyroid cancer, testis cancer, urothelial cancer, lung cancer, melanoma, non-melanoma skin cancer (squamous and basal cell carcinoma), glioma, renal cell cancer (RCC), renal cell carcinoma (RCC), lymphoma (non-Hodgkins' lymphoma (NHL) and Hodgkin's lymphoma (HD)), Acute myeloid leukemia (AML), T-cell Acute Lymphoblastic Leukemia (T-ALL), Diffuse Large B cell lymphoma, testicular germ cell tumors, mesothelioma, esophageal cancer, triple negative breast cancer, Merkel Cells cancer, MSI-high cancer, KRAS mutant tumors, adult T-cell leukemia/lymphoma, pleural mesothelioma, anal SCC, neuroendocrine lung cancer (including neuroendocrine lung carcinoma), HNSCC, NSCLC, NSCL (large cell), NSCLC large cell, NSCLC squamous cell, cervical SCC, malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, adenoid cystic cancer (including adenoid cystic carcinoma), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum resistant microsatellite stable primary peritoneal cancer, PD1 refractory or relapsing, Myelodysplastic syndromes (MDS), gastroesophageal junction cancer, Gastric cancer, fallopian tube cancer, rectal cancer, uveal melanoma, small cell lung cancer, NSCLC adenocarcinoma, atypical carcinoid lung cancer, NSCLC with PDL1>=50% TPS, HNSCC, PD1 refractory or relapsing cancer, chordoma, sarcoma, endometrial sarcoma, chondrosarcoma, uterine sarcoma, plasma cell disorders, multiple myeloma, amyloidosis, AL-amyloidosis, glioblastoma, astrocytoma, Serous adenocarcinoma, and clear cell carcinoma. 
     
     
         76 . (canceled) 
     
     
         77 . (canceled)